Infections by parasites of the genus Plasmodium cause more than 200 million cases of malaria and kill more than 400,000 people annually, the majority of whom are Plasmodium falciparum-infected children in sub- Saharan Africa. Most Plasmodium infections are either asymptomatic or cause only mild malaria. A small proportion of infections progress to severe malaria that can be life threatening. To date, the host factors that predispose patients to developing severe malaria are not known, and it has not been possible to identify risk factors that predict progression from asymptomatic infection to severe malaria. These knowledge gaps hinder discovery of new strategies for the prevention of severe malaria. Using multiple Plasmodium species and mouse strains, we have recently published the novel observation that mice with distinct gut bacterial communities exhibit differences in the severity of malaria and humoral immune response following infection with Plasmodium. Mice resistant to severe malaria exhibit elevated T follicular helper (Tfh) and germinal center (GC) B cell numbers and accelerated antibody class switching following Plasmodium yoelii infection compared to susceptible mice. When mice predicated to develop mild malaria were treated with antibodies that disrupt Tfh-GC B cell communication, they developed high parasite burdens, similar to mice that develop severe malaria. These new observations support the scientific premise of this application and suggest that gut microbiome-mediated modulation of the GC reaction may be a critical mechanism underlying the development of severe malaria. The objective of this proposal is to determine the immunological mechanisms by which the gut microbiome determines susceptibility to severe malaria and identify the specific microbes and metabolites responsible for this outcome. These studies will move the field of malaria pathogenesis forward in new directions and may lead to new translational approaches to control severe malaria, which could, in turn, save the hundreds of thousands of lives lost to severe malaria each year. The central hypothesis of this proposal is that specific microbes and their metabolites modulate GC reactions to determine susceptibility to severe malaria. Our hypothesis will be tested through the following specific aims: Aim 1. Determine the dynamics of gut microbiota-mediated modulation of the GC reaction in mice. Aim 2. Determine the Tfh cell- and GC B cell- intrinsic pathways modulated by the gut microbiota in mice. Aim 3. Identify the specific gut bacteria and their metabolites that determine resistance or susceptibility to severe malaria in mice.